Mitochondrial Signals for the Nucleus

Abstract

What's a transcription factor of the basic helix-loop-helix leucine zipper family doing in the cytoplasm? Sans et al. explored why nearly all of the transcription factor MondoA and its binding partner protein called Mlx is found in the cytoplasm but the protein appears to function as a transcription factor in the nucleus. The authors found that in primary cultures of human muscle or erythroblast cells, MondoA and Mlx were associated with the mitochondria. Inhibition of nuclear shuttling of the proteins with an inhibitor of the CRM1 nuclear export factor caused MondoA (detected by confocal immunofluorescence microscopy) to accumulate in the nucleus. Thus, the authors suspected that MondoA could function to carry signals from the mitochondria to the nucleus. They obtained further circumstantial evidence for such a role from microarray experiments designed to detect genes transcribed in response to MondoA and Mlx. MondoA-Mlx regulated a broad range of targets, which included many genes associated with carbohydrate metabolism. Chromatin immunoprecipitation experiments showed that hexokinase II, 6-phospofructo-2-kinase/fructose-2,6-bisphosphatase 3, and lactate dehydrogenase A--three enzymes important for glycolysis--are direct targets for MondoA-Mlx. Indeed, depletion of MondoA by RNA interference caused a decrease in the rate of glycolysis (measured as the rate of conversion of 5-[ 3 H]glucose to 3 H 2 O). Thus, although other functions are not excluded, the authors propose that MondoA may function as an intracellular metabolic sensor. C. L. Sans, D. J. Satterwhite, C. A. Stoltzman, K. T. Breen, D. E. Ayer, MondoA-Mlx heterodimers are candidate sensors of cellular energy status: Mitochondrial localization and direct regulation of glycolysis. Mol. Cell. Biol. 26 , 4863-4871 (2006). [Abstract] [Full Text]